The present inventors have developed orally effective cephalosporin derivatives having at the 3-position of cephem nucleus a thioalkylthio side chain substituted by a heterocyclic group and disclosed. (see, U.S. patent application Ser. No. 07/729,413, filed on Jul. 12, 1991, now U.S. Pat. No. 5,214,037 and EPO Application Publication No. 0 467 647 A2). Among these antibiotic compounds, a compound having a thioalkylthio side chain substituted by 1,2,3-triazolyl group, i.e., 7.beta.-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-(1,2,3-tri azol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid (hereinafter, it referred to as S-1090), which was obtained as a pale yellowish powder, exhibited a remarkably potent antibacterial activity, and was expected to be a promising candidate as an active ingredient of antibiotic formulations. S-1090 is shown by the following formula: ##STR1##
S-1090, however, was not stable enough to be formulated into medical compositions. The instability of S-1090 was attributable to the following properties of it.
a) S-1090 generally contains water because of the hygroscopic property. The problem is that the water content tends to vary during manufacturing process steps such as pulverization, formulation and the like, which is accompanied by the variation of the content of active ingredient in S-1090-containing pharmaceutical compositions. This can bring about a quality control problem and make the product unreliable with respect to the maintenance of the quality, content of active ingredient and the operability of products. PA1 b) S-1090 produced by an ordinary method is an amorphous powder and is not water-soluble enough to be recrystallized from water, which makes it difficult to remove contaminants contained in the amorphous powder of S-1090. PA1 c) Even dried S-1090 contains residual solvent that is hardly removed to a pharmaceutically acceptable extent. PA1 Conditions for Measurement: Tube; Cu; Voltage, 40 kV; PA1 Current, 20 mA; Sampling angle, 0.02.degree..
The present inventors have made an intensive study to obtain clinically advantageous derivatives of S-1090, which are pharmaceutically stable and contain only a little or slight amount of contaminating solvent, and have found that S-1090 hydrochloride and a crystalline hydrate thereof have the desired properties such as low-toxicity, high-solubility in water, pharmaceutical stability and potent antibacterial activity.